tbuckley/cabot-search huggingface dataset:
CD8+ CD226high T cells in liver metastases dictate the prognosis of colorectal cancer patients treated with chemotherapy and radical surgery
Authors: Julien Viot, Syrine Abdeljaoued, Angélique Vienot, Evan Seffar, Laurie Spehner, Adeline Bouard, Kamal Asgarov, Jean-René Pallandre, Elodie Renaude, Elodie Klajer, Chloé Molimard, Franck Monnien, Frederic Bibeau, Celia Turco, Bruno Heyd, Paul Peixoto, Eric Hervouet, Romain Loyon, Alexandre Doussot, Christophe Borg, Marie Kroemer
Journal: Cellular and Molecular Immunology (2023)

CD226 has been reported to participate in the rescue of CD8+ T cell dysfunction. In this study, we aimed to assess the prognostic value of CD226 in tumor-infiltrating lymphocytes (TILs) derived from colorectal cancer (CRC) liver metastases treated with chemotherapy and radical surgery. TILs from 43 metastases were isolated and analyzed ex vivo using flow cytometry. CD155 and CD3 levels in the tumor microenvironment were assessed by immunohistochemistry. Exploration and validation of biological processes highlighted in this study were performed by bioinformatics analysis of bulk RNA-seq results for 28 CRC liver metastases pretreated with chemotherapy as well as public gene expression datasets. CD226 expression contributes to the definition of the immune context in CRC liver metastases and primary tumors. CD226 on CD8+ T cells was not specifically coexpressed with other immune checkpoints, such as PD1, TIGIT, and TIM3, in liver metastases. Multivariate Cox regression analysis revealed CD226 expression on CD8+ T cells to be an independent prognostic factor (p = 0.003), along with CD3 density at invasion margins (p = 0.003) and TIGIT expression on CD4+ T cells (p = 0.019). CD155 was not associated with the prognostic value of CD226. Gene expression analysis in a validation dataset confirmed the prognostic value of CD226 in CRC liver metastases but not in primary tumors. Downregulation of CD226 on CD8+ TILs in the liver microenvironment was restored by IL15 treatment. Overall, CD226 expression on liver metastasis-infiltrating CD8+ T cells selectively contributes to immune surveillance of CRC liver metastases and has prognostic value for patients undergoing radical surgery.
Mechanical Restraint Use Among Residents of Skilled Nursing Facilities
Authors: Mary E. Tinetti
Journal: JAMA (1991)

The patterns of and risk factors for mechanical restraint use were determined in 12 skilled nursing facilities. Restraints were being used for 59% of residents at the beginning of the study; 31% of remaining residents were restrained during the follow-up year. No facility characteristic was associated with restraint use. The resident characteristics independently associated with initiation of restraints were older age, disorientation, dependence in dressing, greater participation in social activities, and nonuse of antidepressants. Unsteadiness (72%), disruptive behavior such as agitation (41%), and wandering (20%) were the most frequently cited reasons for initiation of restraints. (<i>JAMA</i>. 1991;265:468-471)
CNP Promotes Antiarrhythmic Effects via Phosphodiesterase 2
Authors: Eleder Cachorro, Mario Günscht, Mario Schubert, Mirna S. Sadek, Johanna Siegert, Fabian Dutt, Carla Bauermeister, Susann Quickert, Henrik Berning, Felix Nowakowski, Simon Lämmle, Rebecca Firneburg, Xiaojing Luo, Stephan R. Künzel, Erik Klapproth, Peter Mirtschink, Manuel Mayr, Matthias Dewenter, Christiane Vettel, Jordi Heijman, Kristina Lorenz, Kaomei Guan, Ali El-Armouche, Michael Wagner, Susanne Kämmerer
Journal: Circulation Research (2023)

Background: Ventricular arrhythmia and sudden cardiac death are the most common lethal complications after myocardial infarction. Antiarrhythmic pharmacotherapy remains a clinical challenge and novel concepts are highly desired. Here, we focus on the cardioprotective CNP (C-type natriuretic peptide) as a novel antiarrhythmic principle. We hypothesize that antiarrhythmic effects of CNP are mediated by PDE2 (phosphodiesterase 2), which has the unique property to be stimulated by cGMP to primarily hydrolyze cAMP. Thus, CNP might promote beneficial effects of PDE2-mediated negative crosstalk between cAMP and cGMP signaling pathways. Methods: To determine antiarrhythmic effects of cGMP-mediated PDE2 stimulation by CNP, we analyzed arrhythmic events and intracellular trigger mechanisms in mice in vivo, at organ level and in isolated cardiomyocytes as well as in human-induced pluripotent stem cell-derived cardiomyocytes. Results: In ex vivo perfused mouse hearts, CNP abrogated arrhythmia after ischemia/reperfusion injury. Upon high-dose catecholamine injections in mice, PDE2 inhibition prevented the antiarrhythmic effect of CNP. In mouse ventricular cardiomyocytes, CNP blunted the catecholamine-mediated increase in arrhythmogenic events as well as in I CaL , I NaL , and Ca 2+ spark frequency. Mechanistically, this was driven by reduced cellular cAMP levels and decreased phosphorylation of Ca 2+ handling proteins. Key experiments were confirmed in human iPSC-derived cardiomyocytes. Accordingly, the protective CNP effects were reversed by either specific pharmacological PDE2 inhibition or cardiomyocyte-specific PDE2 deletion. Conclusions: CNP shows strong PDE2-dependent antiarrhythmic effects. Consequently, the CNP-PDE2 axis represents a novel and attractive target for future antiarrhythmic strategies.
Precarious work and the covid-19 pandemic: the need for a gender equality focus
Authors: Tania L King, Humaira Maheen, Yamna Taouk, Anthony D LaMontagne
Journal: BMJ (2023)

<b>Tania King and colleagues</b> argue that lessons learnt from previous crises and an explicit focus on gender should shape responses to reduce inequalities in job losses and sustained employment precarity after the covid-19 pandemic
Ten recommendations for child-friendly visiting policies in critical care
Authors: Maria Brauchle, Teresa Deffner, Peter Nydahl, Alexander Brinkmann, Svenja Dehner, Rolf Dubb, Simon Finkeldei, Birga Gatzweiler, Carsten Hermes, Christian Heyd, Magdalena Hoffmann, Marie-Madlen Jeitziner, Arnold Kaltwasser, Tita Kern, Kathrin Knochel, Lars Krüger, Heiner Melching, Guido Michels, Tilmann Müller-Wolff, Sabrina Pelz, Julian Rudolph, Denise Schindele, Anna-Henrikje Seidlein, Arne Simon, Marina Ufelmann
Journal: Intensive Care Medicine (2023)
Risk prediction in early childhood sonic hedgehog medulloblastoma treated with radiation-avoiding chemotherapy: Evidence for more than 2 subgroups
Authors: Svenja Tonn, Andrey Korshunov, Denise Obrecht, Martin Sill, Michael Spohn, Katja von Hoff, Till Milde, Torsten Pietsch, Tobias Goschzik, Brigitte Bison, Björn-Ole Juhnke, Nina Struve, Dominik Sturm, Felix Sahm, Michael Bockmayr, Carsten Friedrich, André O von Bueren, Nicolas U Gerber, Martin Benesch, David T W Jones, Marcel Kool, Annika K Wefers, Ulrich Schüller, Stefan M Pfister, Stefan Rutkowski, Martin Mynarek
Journal: Neuro-Oncology (2023)

Abstract Background The prognostic impact of clinical risk factors and DNA methylation patterns in sonic hedgehog (SHH)-activated early childhood desmoplastic/nodular medulloblastoma (DMB) or medulloblastoma with extensive nodularity (MBEN) were evaluated to better identify patients at risk for relapse. Methods One hundred and forty-four patients with DMB (n = 99) or MBEN (n = 45) aged &amp;lt;5 years and treated with radiation-sparing approaches, including intraventricular methotrexate in 132 patients were evaluated. Results Patients with DMB had less favorable 5-year progression-free survival than MBEN (5y-PFS, 71% [DMB] vs. 93% [MBEN]). Patients aged &amp;gt;3 years were associated with more unfavorable 5y-PFS (47% [&amp;gt;3 years] vs. 85% [&amp;lt;1 year] vs. 84% [1–3 years]). DNA methylation profiles available (n = 78) were reclassified according to the 2021 WHO classification into SHH-1 (n = 39), SHH-2 (n = 38), and SHH-3 (n = 1). Hierarchical clustering delineated 2 subgroups among SHH-2: SHH-2a (n = 19) and SHH-2b (n = 19). Patients with SHH-2b medulloblastoma were older, predominantly displayed DMB histology, and were more often located in the cerebellar hemispheres. Chromosome 9q losses were more frequent in SHH-2b, while few chromosomal alterations were observed in SHH-2a. SHH-2b medulloblastoma carried a significantly increased relapse risk (5y-PFS: 58% [SHH-2b] vs. 83% [SHH-1] vs. 95% [SHH-2a]). Subclassification of SHH-2 with key clinical and cytogenetic characteristics was confirmed using 2 independent cohorts (total n = 188). Gene mutation analysis revealed a correlation of SHH-2a with SMO mutations. Conclusions These data suggest further heterogeneity within early childhood SHH-DMB/MBEN: SHH-2 splits into a very low-risk group SHH-2a enriched for MBEN histology and SMO mutations, and SHH-2b comprising older DMB patients with a higher risk of relapse.
A phase 1b study of ibrutinib in combination with obinutuzumab in patients with relapsed or refractory chronic lymphocytic leukemia
Authors: Christine E. Ryan, Danielle M. Brander, Paul M. Barr, Svitlana Tyekucheva, Liam R. Hackett, Mary C. Collins, Stacey M. Fernandes, Yue Ren, Yinglu Zhou, Mikaela M. McDonough, Heather A. Walker, Monica R. McEwan, Jeremy S. Abramson, Eric D. Jacobsen, Ann S. LaCasce, David C. Fisher, Jennifer R. Brown, Matthew S. Davids
Journal: Leukemia (2023)
LKB1-Dependent Regulation of TPI1 Creates a Divergent Metabolic Liability between Human and Mouse Lung Adenocarcinoma
Authors: Benjamin D. Stein, John R. Ferrarone, Eric E. Gardner, Jae Won Chang, David Wu, Pablo E. Hollstein, Roger J. Liang, Min Yuan, Qiuying Chen, John S. Coukos, Miriam Sindelar, Bryan Ngo, Steven S. Gross, Reuben J. Shaw, Chen Zhang, John M. Asara, Raymond E. Moellering, Harold Varmus, Lewis C. Cantley
Journal: Cancer Discovery (2023)

KRAS is the most frequently mutated oncogene in human lung adenocarcinomas (hLUAD), and activating mutations frequently co-occur with loss-of-function mutations in TP53 or STK11/LKB1. However, mutation of all three genes is rarely observed in hLUAD, even though engineered comutation is highly aggressive in mouse lung adenocarcinoma (mLUAD). Here, we provide a mechanistic explanation for this difference by uncovering an evolutionary divergence in the regulation of triosephosphate isomerase (TPI1). In hLUAD, TPI1 activity is regulated via phosphorylation at Ser21 by the salt inducible kinases (SIK) in an LKB1-dependent manner, modulating flux between the completion of glycolysis and production of glycerol lipids. In mice, Ser21 of TPI1 is a Cys residue that can be oxidized to alter TPI1 activity without a need for SIKs or LKB1. Our findings suggest this metabolic flexibility is critical in rapidly growing cells with KRAS and TP53 mutations, explaining why the loss of LKB1 creates a liability in these tumors. Utilizing phosphoproteomics and metabolomics in genetically engineered human cell lines and genetically engineered mouse models (GEMM), we uncover an evolutionary divergence in metabolic regulation within a clinically relevant genotype of human LUAD with therapeutic implications. Our data provide a cautionary example of the limits of GEMMs as tools to study human diseases such as cancers. This article is highlighted in the In This Issue feature, p. 799.
Extrachromosomal DNA Amplification Contributes to Small Cell Lung Cancer Heterogeneity and Is Associated with Worse Outcomes
Authors: Lőrinc Sándor Pongor, Christopher W. Schultz, Lorenzo Rinaldi, Darawalee Wangsa, Christophe E. Redon, Nobuyuki Takahashi, Gavriel Fialkoff, Parth Desai, Yang Zhang, Sandra Burkett, Nadav Hermoni, Noa Vilk, Jenia Gutin, Rona Gergely, Yongmei Zhao, Samantha Nichols, Rasa Vilimas, Linda Sciuto, Chante Graham, Juan Manuel Caravaca, Sevilay Turan, Shen Tsai-wei, Vinodh N. Rajapakse, Rajesh Kumar, Deep Upadhyay, Suresh Kumar, Yoo Sun Kim, Nitin Roper, Bao Tran, Stephen M. Hewitt, David E. Kleiner, Mirit I. Aladjem, Nir Friedman, Gordon L. Hager, Yves Pommier, Thomas Ried, Anish Thomas
Journal: Cancer Discovery (2023)

Small-cell lung cancer (SCLC) is an aggressive neuroendocrine lung cancer. Oncogenic MYC amplifications drive SCLC heterogeneity, but the genetic mechanisms of MYC amplification and phenotypic plasticity, characterized by neuroendocrine and nonneuroendocrine cell states, are not known. Here, we integrate whole-genome sequencing, long-range optical mapping, single-cell DNA sequencing, and fluorescence in situ hybridization to find extrachromosomal DNA (ecDNA) as a primary source of SCLC oncogene amplifications and driver fusions. ecDNAs bring to proximity enhancer elements and oncogenes, creating SCLC transcription-amplifying units, driving exceptionally high MYC gene dosage. We demonstrate that cell-free nucleosome profiling can noninvasively detect ecDNA amplifications in plasma, facilitating its genome-wide interrogation in SCLC and other cancers. Altogether, our work provides the first comprehensive map of SCLC ecDNA and describes a new mechanism that governs MYC-driven SCLC heterogeneity. ecDNA-enabled transcriptional flexibility may explain the significantly worse survival outcomes of SCLC harboring complex ecDNA amplifications. MYC drives SCLC progression, but the genetic basis of MYC-driven SCLC evolution is unknown. Using SCLC as a paradigm, we report how ecDNA amplifications function as MYC-amplifying units, fostering tumor plasticity and a high degree of tumor heterogeneity. This article is highlighted in the In This Issue feature, p. 799.
Intratumoral Heterogeneity and Clonal Evolution Induced by HPV Integration
Authors: Keiko Akagi, David E. Symer, Medhat Mahmoud, Bo Jiang, Sara Goodwin, Darawalee Wangsa, Zhengke Li, Weihong Xiao, Joe Dan Dunn, Thomas Ried, Kevin R. Coombes, Fritz J. Sedlazeck, Maura L. Gillison
Journal: Cancer Discovery (2023)

Abstract The human papillomavirus (HPV) genome is integrated into host DNA in most HPV-positive cancers, but the consequences for chromosomal integrity are unknown. Continuous long-read sequencing of oropharyngeal cancers and cancer cell lines identified a previously undescribed form of structural variation, “heterocateny,” characterized by diverse, interrelated, and repetitive patterns of concatemerized virus and host DNA segments within a cancer. Unique breakpoints shared across structural variants facilitated stepwise reconstruction of their evolution from a common molecular ancestor. This analysis revealed that virus and virus–host concatemers are unstable and, upon insertion into and excision from chromosomes, facilitate capture, amplification, and recombination of host DNA and chromosomal rearrangements. Evidence of heterocateny was detected in extrachromosomal and intrachromosomal DNA. These findings indicate that heterocateny is driven by the dynamic, aberrant replication and recombination of an oncogenic DNA virus, thereby extending known consequences of HPV integration to include promotion of intratumoral heterogeneity and clonal evolution. Significance: Long-read sequencing of HPV-positive cancers revealed “heterocateny,” a previously unreported form of genomic structural variation characterized by heterogeneous, interrelated, and repetitive genomic rearrangements within a tumor. Heterocateny is driven by unstable concatemerized HPV genomes, which facilitate capture, rearrangement, and amplification of host DNA, and promotes intratumoral heterogeneity and clonal evolution. See related video: https://vimeo.com/845407469 See related commentary by McBride and White, p. 814. This article is highlighted in the In This Issue feature, p. 799
Fructose Metabolism in Tumor Endothelial Cells Promotes Angiogenesis by Activating AMPK Signaling and Mitochondrial Respiration
Authors: Jian-Hong Fang, Jie-Ying Chen, Jia-Lin Zheng, Hui-Xian Zeng, Jun-Guang Chen, Chen-Hui Wu, Jia-Li Cai, Zhi-Yong Wang, Shi-Mei Zhuang
Journal: Cancer Research (2023)

Abstract Angiogenesis is vital for tumor growth and metastasis. Emerging evidence suggests that metabolic reprogramming in endothelial cells (EC) may affect angiogenesis. Here, we showed that multiple regulators in the fructose metabolism pathway, especially fructose transporter SLC2A5 and fructose-metabolizing enzyme ketohexokinase (KHK), were upregulated in tumor endothelial cells from hepatocellular carcinoma (HCC). In mouse models with hepatoma xenografts or with Myc/sgp53-induced liver cancer, dietary fructose enhanced tumor angiogenesis, tumor growth, and metastasis, which could be attenuated by treatment with an inhibitor of SLC2A5. Furthermore, vessel growth was substantially increased in fructose-containing Matrigel compared with PBS-Matrigel. Inhibiting fructose metabolism in EC cells in vivo using EC-targeted nanoparticles loaded with siRNA against KHK significantly abolished fructose-induced tumor angiogenesis. Fructose treatment promoted the proliferation, migration, and tube formation of ECs and stimulated mitochondrial respiration and ATP production. Elevated fructose metabolism activated AMPK to fuel mitochondrial respiration, resulting in enhanced EC migration. Fructose metabolism was increased under hypoxic conditions as a result of HIF1α-mediated upregulation of multiple genes in the fructose metabolism pathway. These findings highlight the significance of fructose metabolism in ECs for promoting tumor angiogenesis. Restricting fructose intake or targeting fructose metabolism is a potential strategy to reduce angiogenesis and suppress tumor growth. Significance: Fructose metabolism in endothelial cells fuels mitochondrial respiration to stimulate tumor angiogenesis, revealing fructose metabolism as a therapeutic target and fructose restriction as a dietary intervention for treating cancer.
Identification of <scp>Cell‐Specific</scp> Differential <scp>DNA</scp> Methylation Associated With Methotrexate Treatment Response in Rheumatoid Arthritis
Authors: Cameron Adams, Nisha Nair, Darren Plant, Suzanne M. M. Verstappen, Hong L. Quach, Diana L. Quach, Alex Carvidi, Joanne Nititham, Mary Nakamura, Jonathan Graf, Anne Barton, Lindsey A. Criswell, Lisa F. Barcellos
Journal: Arthritis & Rheumatology (2023)

Objective We undertook this study to estimate changes in cell‐specific DNA methylation (DNAm) associated with methotrexate (MTX) response using whole blood samples collected from rheumatoid arthritis (RA) patients before and after initiation of MTX treatment. Methods Patients included in this study were from the Rheumatoid Arthritis Medication Study (n = 66) and the University of California San Francisco Rheumatoid Arthritis study (n = 11). All patients met the American College of Rheumatology RA classification criteria. Blood samples were collected at baseline and following treatment. Disease Activity Scores in 28 joints using the C‐reactive protein level were collected at baseline and after 3–6 months of treatment with MTX. Methylation profiles were generated using the Illumina Infinium HumanMethylation450 and MethylationEPIC v1.0 BeadChip arrays using DNA from whole blood. MTX response was defined using the EULAR response criteria (responders showed good/moderate response; nonresponders showed no response). Differentially methylated positions were identified using the Limma software package and Tensor Composition Analysis, which is a method for identifying cell‐specific differential DNAm at the CpG level from tissue‐level (“bulk”) data. Differentially methylated regions were identified using Comb‐p software. Results We found evidence of differential global methylation between treatment response groups. Further, we found patterns of cell‐specific differential global methylation associated with MTX response. After correction for multiple testing, 1 differentially methylated position was associated with differential DNAm between responders and nonresponders at baseline in CD4+ T cells, CD8+ T cells, and natural killer cells. Thirty‐nine cell‐specific differentially methylated regions associated with MTX treatment response were identified. There were no significant findings in analyses of whole blood samples. Conclusion We identified cell‐specific changes in DNAm that were associated with MTX treatment response in RA patients. Future studies of DNAm and MTX treatment response should include measurements of DNAm from sorted cells. image
Generation of novel oncolytic vaccinia virus with improved intravenous efficacy through protection against complement-mediated lysis and evasion of neutralization by vaccinia virus-specific antibodies
Authors: Namhee Lee, Yun-Hui Jeon, Jiyoon Yoo, Suk-kyung Shin, Songyi Lee, Mi-Ju Park, Byung-Jin Jung, Yun-Kyoung Hong, Dong-Sup Lee, Keunhee Oh
Journal: Journal for ImmunoTherapy of Cancer (2023)

Oncolytic virus immunotherapy has revolutionized cancer immunotherapy by efficiently inducing both oncolysis and systemic immune activation. Locoregional administration has been used for oncolytic virus therapy, but its applications to deep-seated cancers have been limited. Although systemic delivery of the oncolytic virus would maximize viral immunotherapy's potential, this remains a hurdle due to the rapid removal of the administered virus by the complement and innate immune system. Infected cells produce some vaccinia viruses as extracellular enveloped virions, which evade complement attack and achieve longer survival by expressing host complement regulatory proteins (CRPs) on the host-derived envelope. Here, we generated SJ-600 series oncolytic vaccinia viruses that can mimic complement-resistant extracellular enveloped virions by incorporating human CRP CD55 on the intracellular mature virion (IMV) membrane.The N-terminus of the human CD55 protein was fused to the transmembrane domains of the six type I membrane proteins of the IMV; the resulting recombinant viruses were named SJ-600 series viruses. The SJ-600 series viruses also expressed human granulocyte-macrophage colony-stimulating factor (GM-CSF) to activate dendritic cells. The viral thymidine kinase (J2R) gene was replaced by genes encoding the CD55 fusion proteins and GM-CSF.SJ-600 series viruses expressing human CD55 on the IMV membrane showed resistance to serum virus neutralization. SJ-607 virus, which showed the highest CD55 expression and the highest resistance to serum complement-mediated lysis, exhibited superior anticancer activity in three human cancer xenograft models, compared with the control Pexa-Vec (JX-594) virus, after single-dose intravenous administration. The SJ-607 virus administration elicited neutralizing antibody formation in two immunocompetent mouse strains like the control JX-594 virus. Remarkably, we found that the SJ-607 virus evades neutralization by vaccinia virus-specific antibodies.Our new oncolytic vaccinia virus platform, which expresses human CD55 protein on its membrane, prolonged viral survival by protecting against complement-mediated lysis and by evading neutralization by vaccinia virus-specific antibodies; this may provide a continuous antitumor efficacy until a complete remission has been achieved. Such a platform may expand the target cancer profile to include deep-seated cancers and widespread metastatic cancers.
In memoriam: Soldano Ferrone, MD, PhD (1940–2023)
Authors: Theresa Whiteside, Hassane M Zarour
Journal: Journal for ImmunoTherapy of Cancer (2023)

![Graphic][1]</img> Dr Soldano Ferrone died on January 10, 2023, at the age of 82, after an 8-week-long battle with COVID-19. At the time of his death, Soldano was a Professor in Residence, at the Department of Surgery at Massachusetts General Hospital. He had previously held leadership positions